Cancer by Sfakianakis Alexandros: 08/03/17

Πέμπτη 3 Αυγούστου 2017

Issue Information

Cover of this issue. DDX4 is localized on the mitotic spindle. See also Schudrowitz et al. (pages 1612–1619 of this issue).

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89Zr-anti-{gamma}H2AX-TAT but not 18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma

Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of < 5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is found to be futile. We have evaluated the ability of the PET imaging agent, ⁸⁹Zr-anti-H2AX-TAT, to monitor DNA damage in response to fluouracil (5-FU), gemcitabine, or capecitabine treatment in a mouse model of pancreatic cancer. We have also compared the utility of this approach against the standard clinical PET radiotracer, ¹⁸F-FDG. Experimental Design: C57BL/6 mice bearing subcutaneous pancreatic cancer (KPC; B8484) allografts were treated with 5-FU, gemcitabine, or capecitabine. Therapeutic response was monitored by positron emission tomography and ex vivo biodistribution experiments using either ⁸⁹Zr-anti-H2AX-TAT or ¹⁸F-FDG as imaging agents. To further examine the effect of therapeutic response upon uptake of these imaging agents, immunohistochemical analysis of harvested tumour allograft tissue was also performed. Results: Accumulation of ⁸⁹Zr-anti-H2AX-TAT in the tumours of mice that received chemotherapy was higher compared with vehicle-treated mice and was shown to be specifically mediated by H2AX. In contrast, ¹⁸F-FDG did not provide useful indications of therapeutic response. Conclusions: ⁸⁹Zr-anti-H2AX-TAT has shown a superior ability to monitor early therapeutic responses to chemotherapy by PET imaging compared with ¹⁸F-FDG in an allograft model of PDAC in mice.

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FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen

On October 23, 2015, the U.S. Food and Drug Administration approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m² as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks to dacarbazine 1000 mg/m² i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS) of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively. (HR= 0.55; 95% CI: 0.44, 0.70; unstratified log-rank test p<0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A post-marketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was use of PFS as an endpoint to support regular approval of trabectedin.

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A bifunctional MAPK/PI3K antagonist for inhibition of tumor growth and metastasis

Responses to targeted therapies frequently are brief with patients relapsing with drug resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS or BRAF addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multi-kinase activity to achieve tumor control, overcome resistance and prevent metastases through modulation of interconnected cell signaling pathways.

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The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer

OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors.

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Bypassing drug-resistance mechanisms of prostate cancer with small-molecules that target androgen receptor chromatin interactions

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development a series of small molecules that were rationally designed to selectively target the AR DNA binding domain (DBD) and, hence, to directly interfere with AR-DNA interactions. In the current work we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of anti-androgen action of the developed AR-DBD inhibitors, establishing proof-of-principle for targeting DNA-binding domains of nuclear receptors in endocrine cancers.

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Combination Therapy With c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells

Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas (VS) are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSCs) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G₁ cell cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared to the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis, and reveals vulnerable pathways that could be exploited to develop NF2 therapies.

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Inhibition of the V-ATPase by Archazolid A - a new strategy to inhibit EMT

Epithelial-mesenchymal transition (EMT) induces tumor-initiating cells (TICs) which account for tumor recurrence, metastasis and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EMT process and inhibit TIC generation, as shown by a reduced formation of mammospheres and decreased cell motility. As underlying mechanism, V-ATPase-inhibition by Archazolid A disturbs the turnover of E-cadherin: Archazolid abrogates E-cadherin loss during EMT by interfering with its internalization and recycling. Our study elucidates V-ATPase as essential player in EMT by regulating E-cadherin turnover. Archazolid A is suggested as a promising therapeutic agent to block EMT and the generation of TICs.

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Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure

Publication date: Available online 3 August 2017
Source:Cancer Cell
Author(s): Gulfem Dilek Guler, Charles Albert Tindell, Robert Pitti, Catherine Wilson, Katrina Nichols, Tommy KaiWai Cheung, Hyo-Jin Kim, Matthew Wongchenko, Yibing Yan, Benjamin Haley, Trinna Cuellar, Joshua Webster, Navneet Alag, Ganapati Hegde, Erica Jackson, Tracy Leah Nance, Paul Garrett Giresi, Kuan-Bei Chen, Jinfeng Liu, Suchit Jhunjhunwala, Jeff Settleman, Jean-Philippe Stephan, David Arnott, Marie Classon
Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Disruption of the repressive chromatin over LINE-1 elements in DTPs results in DTP ablation, which is partially rescued by reducing LINE-1 expression or function.

Graphical abstract

Teaser

Guler et al. show that drug-tolerant persisters (DTPs), a cancer cell subpopulation surviving lethal drugs, are partly maintained by a repressed chromatin state, prominently at LINE-1 elements. Disrupting the repressive chromatin results in death of DTPs, which is partially rescued by reducing LINE-1 expression.

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Liver Transplantation for Hepatocellular Carcinoma: Kent Hospital Experience

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JCAD Promotes Progression of Non-alcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared to peri-carcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation; whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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Loss of IGF2 gene imprinting in murine prostate promotes widespread neoplastic growth

Loss of imprinting (LOI) is an epigenetic event which relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a pre-malignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways.

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Identification of Novel Breast Cancer Risk Loci

It has been estimated that >1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤ 40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF) >1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population. Through prioritization and stringent selection criteria, we selected 24 SNPs for further genotyping in 1,516 breast cancer cases and 1,189 non-cancer controls. Overall, we identified the JAK2 SNP rs56118985 to be significantly associated with overall breast cancer risk. Subtype analysis performed for patient subgroups defined by ER, PR and HER2 status suggested additional associations of the NOTCH3 SNP rs200504060 and the HIF1A SNP rs142179458 with breast cancer risk. In silico analysis indicated that coding amino acids encoded at these three SNP sites were conserved evolutionarily and associated with decreased protein stability, suggesting a likely impact on protein function. Our results offer proof of concept for identifying novel cancer risk loci from next-generation sequencing data, with iterative data analysis from targeted, whole-exome or whole-genome sequencing a wellspring to identify new SNPs associated with cancer risk.

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Aneuploid cell survival relies upon sphingolipid homeostasis.

Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard of care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacological evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.

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EZH2 palmitoylation mediated by ZDHHC5 in p53 mutant glioma drives malignant development and progression

Gilomas with mutant p53 occurring in 30% of giloma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared to normal brain tissue and that this event to be tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas.

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Relevance of Spatial Heterogeneity of Immune Infiltration for Predicting Risk of Recurrence After Endocrine Therapy of ER+ Breast Cancer

Abstract

Background

Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor–negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined.

Methods

Quantitative immune scores of cell abundance and spatial heterogeneity were computed using a fully automated hematoxylin and eosin–stained image analysis algorithm and spatial statistics for 1178 postmenopausal patients with ER+ breast cancer treated with five years' tamoxifen or anastrozole. The prognostic significance of immune scores was compared with Oncotype DX 21-gene recurrence score (RS), PAM50 risk of recurrence (ROR) score, IHC4, and clinical treatment score, available for 963 patients. Statistical tests were two-sided.

Results

Scores of immune cell abundance were not associated with recurrence-free survival. In contrast, high immune spatial scores indicating increased cell spatial clustering were associated with poor 10-year, early (0–5 years), and late (5–10 years) recurrence-free survival (Immune Hotspot: LR-χ² = 14.06, P < .001, for 0–10 years; LR-χ² = 6.24, P = .01, for 0–5 years; LR-χ² = 7.89, P = .005, for 5–10 years). The prognostic value of spatial scores for late recurrence was similar to that of IHC4 and RS in both populations, but was not as strong as other tests in comparison for recurrence across 10 years.

Conclusions

These results provide a missing link between tumor immunity and disease outcome in ER+ disease by examining tumor spatial architecture. The association between spatial scores and late recurrence suggests a lasting memory of protumor immunity that may impact disease progression and evolution of endocrine treatment resistance, which may be exploited for therapeutic advances.

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Medical Knowledge Assessment by Hematology and Medical Oncology In-Training Examinations Are Better Than Program Director Assessments at Predicting Subspecialty Certification Examination Performance

Abstract

The Accreditation Council for Graduate Medical Education's Next Accreditation System requires training programs to demonstrate that fellows are achieving competence in medical knowledge (MK), as part of a global assessment of clinical competency. Passing American Board of Internal Medicine (ABIM) certification examinations is recognized as a metric of MK competency. This study examines several in-training MK assessment approaches and their ability to predict performance on the ABIM Hematology or Medical Oncology Certification Examinations. Results of a Hematology In-Service Examination (ISE) and an Oncology In-Training Examination (ITE), program director (PD) ratings, demographic variables, United States Medical Licensing Examination (USMLE), and ABIM Internal Medicine (IM) Certification Examination were compared. Stepwise multiple regression and logistic regression analyses evaluated these assessment approaches as predictors of performance on the Hematology or Medical Oncology Certification Examinations. Hematology ISE scores were the strongest predictor of Hematology Certification Examination scores (β = 0.41) (passing odds ratio [OR], 1.012; 95 % confidence interval [CI], 1.008–1.015), and the Oncology ITE scores were the strongest predictor of Medical Oncology Certification Examination scores (β = 0.45) (passing OR, 1.013; 95 % CI, 1.011–1.016). PD rating of MK was the weakest predictor of Medical Oncology Certification Examination scores (β = 0.07) and was not significantly predictive of Hematology Certification Examination scores. Hematology and Oncology ITEs are better predictors of certification examination performance than PD ratings of MK, reinforcing the effectiveness of ITEs for competency-based assessment of MK.

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Flipping The Practice Based Pathology Laboratory—Can It Support Development Of Practitioner Capability For Trainee Pathologists in Gynaecological Cytopathology?

Abstract

This study investigated the role of 'flipping', the practice-based pathology laboratory and classroom to support the development of trainee pathologist practitioners' in the field of gynaecological cytopathology, addressing development of their knowledge and practical application in the clinical setting. Content-rich courses traditionally involve lecture led delivery which restricts tutors from adopting approaches that support greater student engagement in the topic area and application of knowledge to practice. We investigated the role of 'flipping', the practice-based pathology laboratory and classroom where 'virtual lectures' were accessed outside of 'class time' allowing more time for students to engage in active learning under the supervision of a consultant histopathologist. 'Flipping' was used to support two gynaecological cytopathology training courses with cohorts of eight trainee pathologists on the first course and six on the second. Lectures were made available to the trainees to watch before attending the workshops. The workshops consisted of group activities and individual practical exercises allowing trainees to review and report on patient practice cases with the support of their peers and tutors. Focus group sessions were held after each course, allowing trainee pathologists to reflect on their experiences. Discussions were transcribed and thematic analysis was used to capture key themes discussed by the trainees. Trainees' identified that 'flipping' provided them with more time during face-to-face sessions, enabling a greater depth of questioning and engagement with the consultant histopathologists. Having already watched the lectures, trainees were able to attend the sessions having identified areas in which they needed additional support and development. Trainee pathologists reported they had more time to concentrate on developing their skills and practise under the guidance of the consultant histopathologists so developing their capability in gynaecological cytopathology. The role of alternative methods of delivery such as 'flipping' is suggested for short courses designed to support practitioner capability and continued professional development.

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New Approaches to Continuing Medical Education: a QStream (spaced education) Program for Research Translation in Ovarian Cancer

Abstract

Continuing medical education (CME) is challenging and often has limited impact on clinician behavior or patient outcomes. This study examined the impact of an online Qstream education program on senior clinicians to determine its utility for increasing clinician knowledge about the latest guidelines regarding genetic assessment and consideration of genetic testing for women with particular types of ovarian, fallopian tube and primary peritoneal cancer. Participants were recruited into a pilot study that involved responding to case-based scenarios at spaced and repeated intervals. At the completion of the program, semi-structured interviews were conducted to ascertain the impact on their knowledge and referral behavior. Findings from interviews were subject to thematic analysis that involved the identification of categories and themes. Twenty-one participants commenced the program, seventeen completed and twelve participated in semi-structured interviews. Thematic analysis yielded several themes including knowledge change, curriculum and format and changes in referral patterns. A majority of participants (n = 10) agreed the program had helped update their knowledge about referring women, and eight agreed they would now change their referral patterns. The use of QStream as an approach to CME has significant advantages when working with busy clinicians. QStream has a well accepted format and most participants indicated it is very appropriate for disseminating updates to clinical guidelines and protocols. It is important to supplement CME programs with other implementation techniques, such as audit and feedback as multifaceted approaches are more likely to result in behavior change.

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Determinants of Skin Cancer Preventive Behaviors Among Rural Farmers in Iran: an Application of Protection Motivation Theory

Abstract

Skin cancer is one of the most prevalent cancers, worldwide, which happens more among those with more sunlight exposure like farmers. The aim of this study was to explore the determinants of skin cancer preventive behaviors (SCPBs) among rural farmers using Protection Motivation Theory (PMT). In this cross-sectional study, multistage random sampling was employed to enroll 238 farmers referring to rural health houses (HH) in Chaldoran County, Iran. A valid and reliable instrument based on PMT variables was used. Significant correlations were found between all PMT variables with SCPBs (p < 0.05). Hierarchical multiple linear regressions were performed with Protection Motivation and SCPBs as outcome variables. Predictors for these two outcome variables were classified in two different blocks according to their natures. Demographic characteristics (p > 0.05) and PMT constructs (p < 0.001) explained 3 and 63.6 % of the observed variance in Protection Motivation, respectively. Also, no significant effect was found on SCPBs by demographic variables, in the first block (∆R ² = 0.025); however, in the second block, Perceived Susceptibility (p = 0.000), Rewards (p = 0.022), Self-efficacy (p = 0.000), and Response Cost (p = 0.001) were significant predictors of SCPBs (∆R ² = 0.432). Health care providers may consider PMT as a framework for developing educational interventions aiming at improving SCPBs among rural farmers.

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Medical Knowledge Assessment by Hematology and Medical Oncology In-Training Examinations Are Better Than Program Director Assessments at Predicting Subspecialty Certification Examination Performance

Abstract

http://ift.tt/2uoY4o7

Flipping The Practice Based Pathology Laboratory—Can It Support Development Of Practitioner Capability For Trainee Pathologists in Gynaecological Cytopathology?

Abstract

http://ift.tt/2u99IrG

New Approaches to Continuing Medical Education: a QStream (spaced education) Program for Research Translation in Ovarian Cancer

Abstract

http://ift.tt/2wqbD7V

Determinants of Skin Cancer Preventive Behaviors Among Rural Farmers in Iran: an Application of Protection Motivation Theory

Abstract

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Bilateral blindness secondary to optic nerve ischemia from severe amlodipine overdose: a case report

Calcium channel blockers are commonly prescribed medications; calcium channel blocker overdose is becoming increasingly prevalent. The typical presentation of a calcium channel blocker overdose is hypotension ...

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Improved survival in Medicare patients with multiple myeloma: findings from a large nationwide and population-based cohort

Abstract

The aim of this study was to examine whether novel agents proteasome inhibitor bortezomib and immunomodulatory drugs lenalidomide and thalidomide are effective in prolonging overall survival (OS) for patients with newly diagnosed multiple myeloma (MM) in the real-world practice setting. A nationwide and population-based retrospective cohort of elderly patients with advanced newly diagnosed MM from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results–Medicare linked data. Survival was compared between cases in 2005–2009 and in 2000–2004, and between patients treated with anti-MM therapy and the untreated among cases in 2005–2009, using Cox proportional hazards models, Kaplan–Meier methods, and propensity score adjustment to further control for baseline confounding. Of 8839 patients, 4028 (45.6%) cases were in 2000–2004 and 4811 (54.4%) in 2005–2009. OS was significantly longer for patients in 2005–2009 than patients in 2000–2004 (27.9 vs. 20.0 months, P < 0.001). The hazard ratio for OS for cases in 2005–2009 compared with those in 2000–2004 was 0.78 (95% CI 0.74–0.82). Among 4811 cases in 2005–2009, 54% (n = 2587) received anti-MM therapy. Compared to those untreated, OS was significantly longer (41.1 vs. 27.9 months, P < 0.001) and hazard ratio was 0.58 (95% CI 0.54–0.62) in the treated patients. This study demonstrated improved survival in newly diagnosed MM patients in a more recent 5-year cohort compared with those in the previous 5 years. The survival benefit was significant across different demographic and patient characteristics. However, there were still a substantial number of MM patients not receiving anti-MM therapy.

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Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer

Abstract

Background

Twist1 is involved in tumor initiation and progression, which especially contributes to tumor invasion and metastasis. Wogonoside is the main in-vivo metabolite of wogonin, and it is also a natural product with potential treatment effects against cancer.

Methods

In this study, we investigated the in-vitro anti-invasion and in-vivo anti-metastasis effects of wogonoside on breast cancer cells and uncovered its underlying mechanism.

Results

The results showed that wogonoside could suppress the growth and metastasis of breast tumor in the orthotopic model of MDA-MB-231 cells. We found that wogonoside could reduce the overexpression of TNF-α, TRAF2 and TRAF4 in later stage of tumor, and improved tumor microenvironment. Therefore, TNF-α was utilized to induce metastases of breast cancer cell in vitro. Wogonoside could inhibit invasion and migration in TNF-α-induced MDA-MB-231, MDA-MB-435, and BT-474 cells. Mechanically, wogonoside inactivated NF-κB signaling through decreasing the protein expression of TRAF2/4, which further inhibited Twist1 expression. Consequently, wogonoside could down-regulate MMP-9, MMP-2, vimentin and CD44v6 expression in TNF-α-induced MDA-MB-231 and MDA-MB-435 cells. Then, these findings were proved in TNF-α + TGF-β1-induced MCF7 cells.

Conclusions

Wogonoside might be a potential therapeutic agent for the treatment of tumor metastasis in breast cancer.

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The paradigm of tumor shrinkage and rapid liver remnant hypertrophy for conversion of initially unresectable colorectal liver metastasis: a case report and literature review

Abstract

Background

For colorectal liver metastasis (CRLM) patients, hepatic resection is currently the sole cure offering the chance of long-term survival. Tumor shrinkage and planned liver remnant hypertrophy are the two key strategies for conversion of initially unresectable CRLM. First conducted in 2012, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver growth. As a means to induce hypertrophy, portal vein embolization (PVE) has been widely applied before extending hepatectomy. Recently, Peng et al. present a new approach of terminal branches portal vein embolization (TBPVE), offering an efficient way to amplify FLR and making chances for surgery in 2 weeks.

Case presentation

We reported a 61-year-old woman with synchronous hepatic metastasized carcinoma of the colon sigmoideum underwent TBPVE after 6 cycles of neoadjuvant therapy in order to perform a planned right trisectionectomy. Rapid liver remnant hypertrophy and remarkable tumor shrinkage were achieved, and laparoscopic sigmoidectomy and right trisectionectomy were successfully performed. The postsurgical course was uneventful and 7 months of recurrence-free survival have been witnessed.

Conclusions

The dual tactics of tumor shrinkage and planned rapid liver remnant hypertrophy will make concerted efforts to further increase the clinical candidacy for curative resection, which are valuable for further investigation.

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Glioblastoma—Unraveling the Threads: A Q&A with Drs. Mark Gilbert and Terri Armstrong of the NIH Neuro-Oncology Branch

Progress against the brain cancer glioblastoma has been slow. Drs. Mark Gilbert and Terri Armstrong of NCI's Neuro-Oncology Branch discuss why and what's being done to change that.

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Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect

Abstract

Purpose

Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics. The current study was performed to evaluate the pharmacokinetics and safety of this novel formulation in healthy volunteers.

Methods

The study was conducted in 11 healthy men aged 47–57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data were compared with pharmacokinetic and safety data reported for 1000 mg Zytiga, the marketed drug.

Results

The novel formulation of AA allows rapid absorption of the compound with t _max values within 1 hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated; actually, a slight, but statistically significant negative food effect was observed. Variability of exposure was significantly reduced when compared to Zytiga. AA administered in the novel formulation was well tolerated with no IMP-related safety AEs reported.

Conclusion

The novel formulation might allow a 75% dose reduction with significant reduction of inter-individual variability. The negative food effect observed requires further investigations; however, elimination of the significant positive food effect could be adequate to negate the restriction of a food label.

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The efficacy of lymphaticovenular anastomosis in breast cancer-related lymphedema

Abstract

Introduction

Lymphedema can be a debilitating condition, causing a great decrease in a person's quality of life (QoL). Treatment with lymphaticovenular anastomosis (LVA), in which an anastomosis is created between the lymphatic and venous system, may attenuate lymphedema symptoms and reduce swelling. In this study, we share the results using LVA to treat breast cancer-related lymphedema (BCRL) at our institution.

Materials and methods

Patients were eligible for inclusion if they suffered from unilateral BCRL, if functional lymphatics were available, if compression therapy was used for at least 6 months, and if the follow-up was 12 months at minimum. Lymph vessel functionality was assessed preoperatively using indocyanine green (ICG). During surgery, 1–3 anastomoses were created and shunt patency was confirmed using ICG. Arm volumes were measured before surgery and at 6- and 12-month follow-up. QoL was measured before surgery and at 6-month follow-up. Arm volume differences between the healthy arm and affected arm were compared between the time points.

Results

Twenty-nine consecutive female patients with unilateral BCRL were included. The preoperative mean difference in arm volumes was 701 ± 435 ml (36.9%). This was reduced to 496 ± 302 ml (24.7%) at 6-month follow-up (p = 0.00). At 12-month follow-up, the mean difference in arm volume was 467 ± 303 ml (23.5%) (p = 0.02). The overall perceived QoL was increased from 5.8 ± 1.1 to 7.4 ± 0.7 (p = 0.00). The functionality score decreased from 2.2 to 1.8 (p = 0.00), the appearance score decreased from 2.6 to 1.9 (p = 0.00), the symptoms score decreased from 2.8 to 1.8 (p = 0.00), and the mood score decreased from 2.7 to 1.5 (p = 0.00). Fifteen patients (53.6%) were able to discontinue the use of compression garment.

Conclusion

Treatment with LVAs is effective in reducing arm volume difference in patients suffering from BCRL. Although no complete reduction of the edema was achieved at 12-month follow-up, the procedure significantly increased the patients' QoL.

http://ift.tt/2v3c48O

Response Letter

http://ift.tt/2vlwz3m

Predictors of distress in female breast cancer survivors: a systematic review

Abstract

Purpose

Unmanaged distress has been shown to adversely affect survival and quality of life in breast cancer survivors. Fortunately, distress can be managed and even prevented with appropriate evidence-based interventions. Therefore, the objective of this systematic review was to synthesize the published literature around predictors of distress in female breast cancer survivors to help guide targeted intervention to prevent distress.

Methods

Relevant studies were located by searching MEDLINE, Embase, PsycINFO, and CINAHL databases. Significance and directionality of associations for commonly assessed candidate predictors (n ≥ 5) and predictors shown to be significant (p ≤ 0.05) by at least two studies were summarized descriptively. Predictors were evaluated based on the proportion of studies that showed a significant and positive association with the presence of distress.

Results

Forty-two studies met the target criteria and were included in the review. Breast cancer and treatment-related predictors were more advanced cancer at diagnosis, treatment with chemotherapy, longer primary treatment duration, more recent transition into survivorship, and breast cancer recurrence. Manageable treatment-related symptoms associated with distress included menopausal/vasomotor symptoms, pain, fatigue, and sleep disturbance. Sociodemographic characteristics that increased the risk of distress were younger age, non-Caucasian ethnicity, being unmarried, and lower socioeconomic status. Comorbidities, history of mental health problems, and perceived functioning limitations were also associated. Modifiable predictors of distress were lower physical activity, lower social support, and cigarette smoking.

Conclusions

This review established a set of evidence-based predictors that can be used to help identify women at higher risk of experiencing distress following completion of primary breast cancer treatment.

http://ift.tt/2fcxAnB

Development of a Ki-67-based clinical trial assay for neoadjuvant endocrine therapy response monitoring in breast cancer

Abstract

Purpose

The recent publication of the ACOSOG Z1031 trial results demonstrated that Ki-67 proliferation marker-based neoadjuvant endocrine therapy response monitoring could be used for tailoring the use of adjuvant chemotherapy in ER+HER2-negative breast cancer patients. In this paper, we describe the development of the Ki-67 clinical trial assay used for this study.

Methods

Ki-67 assay assessment focused on reproducing a 2.7% Ki-67 cut-point (CP) required for calculating the Preoperative Endocrine Prognostic Index and a 10% CP for poor endocrine therapy response identification within the first month of neoadjuvant endocrine treatment. Image analysis was assessed to increase the efficiency of the scoring process. Clinical outcome concordance for two independent Ki-67 scores was the primary performance metric.

Results

Discordant scores led to a triage approach where cases with complex histological features that software algorithms could not resolve were flagged for visual point counting (17%). The final Ki-67 scoring approach was run on T1/2 N0 cases from the P024 and POL trials (N = 58). The percent positive agreement for the 2.7% CP was 87.5% (95% CI 61.7–98.5%); percent negative agreement 88.9% (95% CI: 65.3–98.6%). Minor discordance did not affect the ability to predict similar relapse-free outcomes (Log-Rank P = 0.044 and P = 0.055). The data for the 10% early triage CP in the POL trial were similar (N = 66), the percentage positive agreement was 100%, and percent negative agreement 93.55% (95% CI: 78.58–99.21%). The independent survival predictions were concordant (Log-rank P = 0.0001 and P = 0.01).

Conclusions

We have developed an efficient and reproducible Ki-67 scoring system that was approved by the Clinical Trials Evaluation Program for NCI-supported neoadjuvant endocrine therapy trials. Using the methodology described here, investigators are able to identify a subgroup of patients with ER+HER2-negative breast cancer that can be safely managed without the need of adjuvant chemotherapy.

http://ift.tt/2v315w5

Pleomorphic lobular carcinoma in situ of the breast: a single institution experience with clinical follow-up and centralized pathology review

Abstract

Purpose

The natural history of pleomorphic lobular carcinoma in situ (PLCIS) remains largely unknown.

Methods

A pathology database search (1995–2012) was performed to identify patients diagnosed with an LCIS variant. Patients with synchronous breast cancer and/or no evidence of pleomorphism were excluded. Original slides were re-evaluated by three pathologists to identify a consensus cohort of PLCIS. Borderline lesions with focal atypia were classified as LCIS with pleomorphic features (LCIS-PF). Clinical data were obtained from medical records.

Results

From 233 patients, we identified 32 with an LCIS variant diagnosis and no concurrent breast cancer. Following review, 16 cases were excluded due to lack of pleomorphism. The remaining 16 were classified as PLCIS (n = 11) and LCIS-PF (n = 5). 12/16 patients were treated with surgical excision ± chemoprevention. Patients with a prior breast cancer history and those having mastectomy were excluded from outcome analysis. Among the remaining 7 patients with PLCIS/LCIS-PF, 4/7 (57%) developed ipsilateral breast cancer at a median follow-up of 67 months. Median age at the time of breast cancer diagnosis was 56 years old and median time from PLCIS/LCIS-PF to cancer diagnosis was 59 months (range 45–66 months). The four cancers included 1 invasive lobular carcinoma (ILC), 1 microinvasive ILC, 1 invasive ductal carcinoma, and 1 ductal carcinoma in situ.

Conclusions

We confirm that PLCIS in isolation is indeed a rare entity, further contributing to the difficulty in determining the actual risk conferred by this lesion. Long-term follow-up data on larger cohorts are needed to define standardized management and outcomes for patients with PLCIS.

http://ift.tt/2vmgGJN

Antitumor activity and safety profile of weekly carboplatin plus paclitaxel in metastatic breast cancer: a ten-year, monocentric, retrospective study

Abstract

Background

Taxanes are a mainstay in the treatment of metastatic breast cancer (mBC). Combination chemotherapy, including platinum–taxens doublets, can improve tumor responses and progression-free survival (PFS), but is associated with more toxicities and an uncertain benefit in terms of overall survival (OS).

Methods

We performed a retrospective study on 274 consecutive patients with mBC treated at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, during the decade 2007–2016 with the combination of carboplatin AUC 2 plus paclitaxel 80 mg/m², both given on days 1 and 8 in every 21-day cycle.

Results

264 patients were evaluable for treatment safety and activity. The objective response rate (ORR) was 44.7%. Median PFS and OS were 8.6 and 23.7 months, respectively. Triple-negative breast cancer (TNBC) patients had significantly lower PFS and OS times compared to other biology groups. At multivariable analysis, previous exposure to taxanes, HR-positive HER2-negative biology, a higher number of metastatic sites, and de novo metastatic disease at diagnosis were associated with reduced PFS, while receiving maintenance therapy correlated with improved PFS. Overall, the treatment was quite well tolerated, with 10.2% of patients discontinuing one or both drugs because of adverse events (AEs). G3–G4 neutropenia occurred in 16.8% of patients, while the incidence of febrile neutropenia was 2.3%.

Conclusions

Weekly carboplatin–paclitaxel regimen is active and well tolerated in mBC treatment. Prospective studies should be conducted to compare its efficacy and tolerability with standard single-agent paclitaxel or docetaxel treatment schedules, as well as with more recent combination regimens.

http://ift.tt/2v37Gqs

Erratum to: Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial

http://ift.tt/2fbQOKk

COX2 induction: a mechanism of endocrine breast cancer resistance?

Abstract

Purpose

Urine prostaglandin E2 (PGE2) levels have shown to be a risk factor of breast cancer, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to be beneficial in preventing breast cancer risk and/or recurrence with or without aromatase inhibitors. We hypothesized that the use of an aromatase inhibitor triggers the activation of the inflammatory pathway via release of PGE2.

Methods

A single oral 25 mg dose of an aromatase inhibitor (exemestane) was given to 14 healthy postmenopausal female volunteers. Blood and urine samples were collected between 0 and 72 h post-dosing for pharmacokinetic and pharmacodynamic analysis.

Results

Our findings showed that urine PGE2 levels were markedly increased 72 h after exemestane administration (average pre-dosing PGE2 levels, 4061.1 pg/mL vs. post-dosing average PGE2 levels, 10732.5 pg/mL, P = 0.001, Wilcoxon Rank Test). Out of 14 subjects enrolled in the study, one subject showed no change in PGE2; another showed a 23-fold decreased in PGE2; and the remaining 12 showed an average of 8.4-fold increase in PGE2 levels (range 1.3–30.5, standard deviation 9.2) after exemestane administration. We found no statistically significant correlations between fold increase in urine PGE2 levels and the pharmacokinetics of either exemestane or 17-hydroexemestane (major in vivo metabolite of exemestane).

Conclusion

Our results indicate that one of the pharmacological effects to aromatase inhibitors (e.g., exemestane) involves the activation of the inflammatory pathway via release of PGE2. Further in vitro mechanistic and in vivo translational studies designed to elucidate the role of this newly discovered effect are now warranted.

http://ift.tt/2vmHQ3n

A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104)

Abstract

Purpose

Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease.

Methods

In Phase I, the SAHA dose was modified in cohorts of 3–6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated.

Results

The recommended dose was determined to be 200 mg twice a day on days 1–14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment.

Conclusions

In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.

http://ift.tt/2fcln2p

The financial impact and drivers of hospital charges in contralateral prophylactic mastectomy and reconstruction: a Nationwide Inpatient Sample hospital analysis

Abstract

Purpose

Rates of contralateral prophylactic mastectomy (CPM) have increased over the last decade; it is important for surgeons and hospital systems to understand the economic drivers of increased costs in these patients. This study aims to identify factors affecting charges in those undergoing CPM and reconstruction.

Methods

Analysis of the Healthcare Cost and Utilization Project National Inpatient Sample was undertaken (2009–2012), identifying women aged ≥18 with unilateral breast cancer undergoing unilateral mastectomy with CPM and immediate breast reconstruction (IBR) (CPM group), in addition to unilateral mastectomy and IBR alone (UM group). Generalized linear modeling with gamma regression and a log-link function provided mean marginal hospital charge (MMHC) estimates associated with the presence or absence of patient, hospital and operative characteristics, postoperative complications, and length of stay (LOS).

Results

Overall, 70,695 women underwent mastectomy and reconstruction for unilateral breast cancer; 36,691 (51.9%) in the CPM group, incurring additional MMHCs of $20,775 compared to those in the UM group (p < 0.001). In the CPM group, MMHCs were reduced in those aged >60 years (p < 0.001), while African American or Hispanic origin increased MMHCs (p < 0.001). Diabetes, depression, and obesity increased MMHCs (p < 0.001). MMHCs increased with larger (p < 0.001) hospitals, Western location (p < 0.001), greater household income (p < 0.001), complications (p < 0.001), and increasing LOS (p < 0.001). MMHCs decreased in urban teaching hospitals and Midwest or Southern regions (p < 0.001).

Conclusion

There are many patient and hospital factors affecting charges; this study provides surgeons and hospital systems with transparent, quantitative charge data in patients undergoing contralateral prophylactic mastectomy and immediate breast reconstruction.

http://ift.tt/2v2RnKc

Antibody-based therapies for the treatment of brain metastases from HER2-positive breast cancer: time to rethink the importance of the BBB?

http://ift.tt/2v3esMI

Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes

Abstract

Purpose

We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy.

Methods

This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case–control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy.

Results

Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11–25% OR 2.50, 95% CI 1.94–3.22 vs. OR 2.03, 95% CI 1.70–2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41–0.70 vs. OR 0.71, 95% CI 0.59–0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11–25% OR 3.24, 95% CI 1.75–6.00 vs. OR 1.93, 95% CI 1.25–2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21–0.85 vs. OR 0.56, 95% CI 0.35–0.89, p-heterogeneity = 0.01), even though the interaction was not significant.

Conclusion

Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

http://ift.tt/2hrvgKo

Preferences for breast cancer risk reduction among BRCA1/BRCA2 mutation carriers: a discrete-choice experiment

Abstract

Purpose

Unaffected women who carry BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors.

Methods

A discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25–55 years with germline BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group.

Results

Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention.

Conclusions

Women with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.

http://ift.tt/2hri9sx

Pretreatment glycemic control status is an independent prognostic factor for cervical cancer patients receiving neoadjuvant chemotherapy for locally advanced disease

Abstract

Background

To investigate whether poor glycemic control status has a negative impact on survival outcomes and tumor response to chemotherapy in patients receiving neoadjuvant chemotherapy (NACT) for locally advanced cervical cancer (LACC).

Methods

A retrospective cohort study was conducted to examine LACC patients undergoing NACT and radical hysterectomy between 2002 and 2011. Patients were divided into three groups: patients without diabetes mellitus (DM), diabetic patients with good glycemic control, and diabetic patients with poor glycemic control. Hemoglobin A_1c (HbA_1c) levels were used to indicate glycemic control status. Recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed using log-rank tests and Cox proportional hazards models.

Results

In total, 388 patients were included and had a median follow-up time of 39 months (range: 4–67 months). Diabetes mellitus (DM) was diagnosed in 89 (22.9%) patients, only 35 (39.3%) of whom had good glycemic control prior to NACT (HbA_1c < 7.0%). In survival analysis, compared with patients with good glycemic control and patients without DM, patients with poor glycemic control (HbA_1c ≥ 7.0%) exhibited decreased recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). In multivariate analysis, HbA_1c ≥ 7.0% was identified as an independent predictor for decreased RFS (hazard ratio [HR] = 3.33, P < 0.0001), CSS (HR = 3.60, P < 0.0001) and OS (HR = 4.35, P < 0.0001). In the subgroup of diabetic patients, HbA_1c ≥ 7.0% prior to NACT had an independent negative effect on RFS (HR = 2.18, P = 0.044) and OS (HR = 2.29, P = 0.012). When examined as a continuous variable, the HbA_1c level was independently associated with decreased RFS (HR = 1.39, P = 0.002), CSS (HR = 1.28, P = 0.021) and OS (HR = 1.27, P = 0.004). Both good (odds ratio [OR] = 0.06, P < 0.0001) and poor glycemic control (OR = 0.04, P < 0.0001) were independently associated with a decreased likelihood of complete response following NACT.

Conclusions

Poor glycemic control is an independent predictor of survival and tumor response to chemotherapy for patients receiving NACT for LACC.

http://ift.tt/2v3m1mK

Frequency of Human papillomavirus in women attending cervical cancer screening program in Chile

Abstract

Background

Human papillomavirus (HPV) is the etiological factor for cervical cancer and its precursor lesions. The characterization of HPV genotypes in preneoplastic lesions and cervical cancer could establishes the effectiveness of vaccination plan in Chilean population. The aim of this study was to determine HPV frequency in a group of women including in a cervical screening program in the public health care system in Chile.

Methods

We analyzed 985 cervical smears samples from women with different histological diagnosis, attending to public health care in Temuco-Chile between 2004 and 2012, to detect HPV genotypes, through PCR followed by reverse line blotting assay.

Results

HPV was found present in 80.8% (n = 796) of samples. Only a 5.6% of 985 samples were infected with a low-risk HPV, considering multiple infections. 10.5% (n = 8/76) of normal cervical epithelia, 83.5% (n = 208/249) and 87.6% (n = 557/636) of low and high grade squamous intraepithelial lesions, respectively, and 95.8% (n = 23/24) of squamous cervical carcinomas tested positive for HPV. HPV 16 was the most frequent genotype found (Overall 44.9%, n = 442/985; SCC: 62.5%, n = 15/24). A high variability of HPV types was also found in preneoplastic lesions, whereas there was a selection of genotypes in neoplasia. Also, there was a higher risk of infection with HPV 16 in women ≤26 years and 34–41 years old (p < 0.05), meanwhile infections with HPV 16 or HPV 18 have related with cancer development (p < 0.01).

Conclusions

These data provide further information about the frequency of HPV genotypes in women with cervical lesions in Chile, and the introduction of new targeted vaccines against a wider spectrum of HPV is suggested.

http://ift.tt/2vmfXbo

18 F-FDG PET/CT response in a phase 1/2 trial of nab- paclitaxel plus gemcitabine for advanced pancreatic cancer

Abstract

Background

Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine.

Methods

Tumors were measured by [¹⁸F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m² plus gemcitabine 1000 mg/m² on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline.

Results

Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m² and 125 mg/m² cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m² had a 4-month survival advantage over those who received 100 mg/m². All patients in the nab-paclitaxel 125 mg/m² cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m² cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman r _s = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m² cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%.

Conclusions

The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m² plus gemcitabine 1000 mg/m² for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC.

Trial registration

NCT00398086.

http://ift.tt/2vtkdpv

Detecting anomalies in a deliberately biased tomotherapy plan: Comparison of two patient-specific quality assurance processes involving ArcCHECK® and Gafchromic® EBT3 films

Publication date: Available online 2 August 2017
Source:Cancer/Radiothérapie
Author(s): F. Werlé, N. Dehaynin, C. Niederst, D. Jarnet, M. Gantier, D. Karamanoukian, P. Meyer
PurposeThis work proposes a comparative evaluation of two of our patient-specific quality assurance processes involving ArcCHECK^® (Sun Nuclear) and Gafchromic^® EBT3 films (Ashland) in order to determine which detector is able to most effectively detect an anomaly in a deliberately biased tomotherapy plan.Material and methodsA complex clinical head and neck tomotherapy plan was deliberately biased by introducing six errors: multileaf collimator leaf positional errors by leaving one and two central leafs closed during the whole treatment, initial radiation angle errors (+0.5° and +1.0°) and multileaf collimator leafs opening time errors (+0.5% and +1.0%). For each error-induced plan, comparison of ArcCHECK^® with Gafchromic^® EBT3 films (20.3×25.4cm²) was performed through two methods: a dose matrices subtraction study and a gamma index analysis.ResultsThe dose matrices subtraction study shows that our ArcCHECK^® processing is able to detect all the six induced errors contrary to the one using films, which are only able to detect the two biases involving multileaf collimator leaf positional errors. The gamma index analysis confirms the previous method, since it shows all six errors induced in the reference plan seem to be widely detected with ArcCHECK^® with the more restrictive 1%/1mm gamma criterion, whereas films may only be able to detect biases in relation to multileaf collimator leaf positional errors. It also shows the common 3%/3mm gamma criterion does not allow deciding between both detectors in the detection of the six induced biases.ConclusionBoth comparative methods showed ArcCHECK^® processing is more suitable to detect the six errors introduced in the reference treatment plan.

http://ift.tt/2u7AnW7

Training Needs of Clinical and Research Professionals to Optimize Minority Recruitment and Retention in Cancer Clinical Trials

Abstract

The study of disparities in minority recruitment to cancer clinical trials has focused primarily on inquiries among minority patient populations. However, clinical trial recruitment is complex and requires a broader appreciation of the multiple factors that influence minority participation. One area that has received little attention is minority recruitment training for professionals who assume various roles in the clinical trial recruitment process. Therefore, we assessed the perspectives of cancer center clinical and research personnel on their training and education needs toward minority recruitment for cancer clinical trials. Ninety-one qualitative interviews were conducted at five U.S. cancer centers among four stakeholder groups: cancer center leaders, principal investigators, referring clinicians, and research staff. Interviews were recorded and transcribed. Qualitative analyses focused on response data related to training for minority recruitment for cancer clinical trials. Four prominent themes were identified: (1) Research personnel are not currently being trained to focus on recruitment and retention of minority populations; (2) Training for minority recruitment and retention provides for a specific focus on factors influencing minority research participation; (3) Training on cultural awareness may help to bridge cultural gaps between potential minority participants and research professionals; (4) Views differ regarding the importance of research personnel training designed to focus on recruitment of minority populations. There is a lack of systematic training for minority recruitment. Many stakeholders acknowledged the benefits of minority recruitment training and welcomed training that focuses on increasing cultural awareness to increase the participation of minorities in cancer clinical trials.

http://ift.tt/2v2EBv3

Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis

Abstract

Background

Ferritin plays a central role in the intracellular iron metabolism; the molecule is a nanocage of 24 subunits of the heavy and light types. The heavy subunit (FHC) is provided of a ferroxidase activity and thus performs the key transformation of iron in a non-toxic form. Recently, it has been shown that FHC is also involved in additional not iron-related critical pathways including, among the others, p53 regulation, modulation of oncomiRNAs expression and chemokine signalling. Epithelial to mesenchymal transition (EMT) is a cellular mechanism by which the cell acquires a fibroblast-like phenotype along with a decreased adhesion and augmented motility. In this work we have focused our attention on the role of the FHC on EMT induction in the human cell lines MCF-7 and H460 to elucidate the underlying molecular mechanisms.

Methods

Targeted silencing of the FHC was performed by lentiviral-driven shRNA strategy. Reconstitution of the FHC gene product was obtained by full length FHC cDNA transfection with Lipofectamine 2000. MTT and cell count assays were used to evaluate cell viability and proliferation; cell migration capability was assayed by the wound-healing assay and transwell strategy. Quantification of the CXCR4 surface expression was performed by flow cytometry.

Results

Experimental data indicated that FHC-silenced MCF-7 and H460 cells (MCF-7^shFHC, H460^shFHC) acquire a mesenchymal phenotype, accompanied by a significant enhancement of their migratory and proliferative capacity. This shift is coupled to an increase in ROS production and by an activation of the CXCR4/CXCL12 signalling pathway. We present experimental data indicating that the cytosolic increase in ROS levels is responsible for the enhanced proliferation of FHC-silenced cells, while the higher migration rate is attributable to a dysregulation of the CXCR4/CXCL12 axis.

Conclusions

Our findings indicate that induction of EMT, increased migration and survival depend, in MCF-7 and H460 cells, on the release of FHC control on two pathways, namely the iron/ROS metabolism and CXCR4/CXCL12 axis. Besides constituting a further confirmation of the multifunctional nature of FHC, this data also suggest that the analysis of FHC amount/function might be an important additional tool to predict tumor aggressiveness.

http://ift.tt/2v2yCqs

Treating cancerous large airway stenosis with staging radioactive particle implantation guided by computed tomography and fiber bronchoscopy: a clinical study

Abstract

Background

The purpose of this study is to investigate the clinical effectiveness of staging radioactive particle implantation guided by computed tomography (CT) and fiber–optic bronchoscopy in treating cancerous large airway stenosis.

Methods

A total of 102 patients were included; 57 had undergone staging radioactive particle implantation guided by CT and fiber bronchoscopy and 45 did not. Patients were evaluated by CT and fiber–optic bronchoscopy to determine the feasibility of the implantation of radioactive seeds for the treatment of cancerous large airway stenosis. The treatment planning system (TPS) was used to plan the doses. Radioactive seeds were implanted using fiber–optic bronchoscopy. One week later, CT-guided implantation of radioactive seeds was performed.

Results

The clinical evaluation showed complete, partial, slight, and non-response in 38, 14, 5, and 0 patients, respectively. None of the patients were found with serious complications. The diameter of the affected airway, Karnofsky score, dyspnea index, survival, and quality of life of the patients in both groups was significantly higher and significantly different after the treatment (P < 0.05). The dyspnea index was significantly lower in the treatment group as compared with the control group (P < 0.001).

Conclusion

CT- and fiber bronchoscopy-guided staging radioactive particle implantation has definite treatment effectiveness in treating cancerous large airway stenosis. It should be widely used in clinical practices.

http://ift.tt/2hrA1nh

Photon and proton radiotherapy utilization in a population of over 100 million commercially insured patients

Publication date: Available online 2 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Mark R. Waddle, Terence T. Sio, Holly K. Van Houten, Robert L. Foote, Sameer R. Keole, Steven E. Schild, Nadia Laack, Thomas B. Daniels, William Crown, Nilay D. Shah, Robert C. Miller
This is the largest and most geographically diverse description of RT utilization to date. Proton beam utilization remains low and has had little impact on overall utilization compared to IMRT. The utilization rate for pediatric patients remains low and the greatest change in RT use was the increase in IMRT for prostate cancer. Our findings indicate that overall utilization of proton therapy has been low and that its use has likely had little impact on national expenditures on cancer care in the current environment.

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Novel approaches to the prediction, diagnosis and treatment of cardiac late effects in survivors of childhood cancer: a multi-centre observational study

Abstract

Background

Anthracycline-induced cardiac toxicity is a cause of significant morbidity and early mortality in survivors of childhood cancer. Current strategies for predicting which children are at greatest risk for toxicity are imperfect and diagnosis of cardiac injury is usually made relatively late in the natural history of the disease. This study aims to identify genomic, biomarker and imaging parameters that can be used as predictors of risk or aid in the early diagnosis of cardiotoxicity.

Methods

This is a prospective longitudinal cohort study that recruited two cohorts of pediatric cancer patients at six participating centres: (1) an Acute Cohort of children newly diagnosed with cancer prior to starting anthracycline therapy (n = 307); and (2) a Survivor Cohort of long-term survivors of childhood cancer with past exposure to anthracycline (n = 818). The study team consists of three collaborative cores. The Genomics Core is identifying genomic variations in anthracycline metabolism and in myocardial response to injury that predispose children to treatment-related cardiac toxicity. The Biomarker Core is identifying existing and novel biomarkers that allow for early diagnosis and prognosis of anthracycline-induced cardiac toxicity. The Imaging Core is identifying echocardiographic and cardiac magnetic resonance (CMR) imaging parameters that correspond to early signs of cardiac dysfunction and remodeling and precede global dysfunction and clinical symptoms. The data generated by the cores will be combined to create an integrated risk-prediction model aimed at more accurate identification of children who are most susceptible to anthracycline toxicity.

Discussion

We aim to identify genomic risk factors that predict risk for anthracycline cardiotoxicity pre-exposure and imaging and biomarkers that facilitate early diagnosis of cardiac injury. This will facilitate a personalized approach to identifying at-risk children with cancer who may benefit from cardio- protective strategies during therapy, and closer surveillance and earlier initiation of medications to preserve heart function after cancer therapy.

Trial registration

NCT01805778. Registered 28 February 2013; retrospectively registered.

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Bilateral pneumothoraces following acupuncture

A 50-year-old woman was brought to the emergency department with shortness of breath and chest tightness following acupuncture to her upper back for a chronically painful left shoulder. She had symptoms of respiratory distress and chest X-ray revealed bilateral pneumothoraces. Symptoms resolved after insertion of bilateral Seldinger chest drains. She was admitted to the Cardiothoracic Surgery ward, chest drains were removed on the second and third days and the patient was discharged from hospital after 3 days. Clinicians and acupuncturists should be aware of this adverse event following acupuncture.

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Poland syndrome: a case report

Description

Poland syndrome (PS) is a rare chest wall developmental anomaly characterised by ipsilateral agenesis/hypoplasia of the sternocostal head of pectoralis major, hypoplasia of nipple or breast, absence of subcutaneous fat, multiple rib abnormalities, elevated and rotated scapula (Sprengel deformity) and ipsilateral digit abnormalities (brachydactyly, syndactyly). These findings vary and all are rarely found in a single individual.

Our case involves an 8-year-old boy with no medical history who presented for evaluation of chronic rhinitis. There was no breathing or cardiac complaints on review of systems. Physical examination showed chest asymmetry with right anterior chest wall depression and flattening of the right pectoral region with displaced nipple (figure 1). Abduction of the shoulders showed absence of the sternocostal head of pectoralis major. Hand examination did not show any signs of ipsilateral digital abnormality.

Figure 1

Chest asymmetry with right anterior chest wall depression and...

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POEMS syndrome in a patient with rheumatoid arthritis

Multiple myeloma has been reported to be associated with rheumatoid arthritis (RA). POEMS syndrome is a rare variant of multiple myeloma and is characterised by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. We report the case of a 67-year-old patient with RA who developed numbness and tingling in both legs due to polyneuropathy. CT showed a massive right pleural effusion and a sclerotic lesion in the right ninth rib. Histopathological examination of the rib revealed IgA lambda-type plasmacytoma. Serum vascular endothelial growth factor was extremely high at 5530 pg/mL. We made a diagnosis of POEMS syndrome. A literature search of the PubMed database identified only two documented cases of POEMS syndrome in patients with RA. Neuropathies are reportedly more frequent in patients with RA than in the general population. Rheumatologists should consider POEMS syndrome in patients with RA and neurological symptoms.

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Acute interstitial nephritis and DRESS syndrome without eosinophilia associated with cefepime

Description

The drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is a potentially life-threatening drug-induced reaction characterised by a severe skin eruption, fever, haematological abnormalities (eosinophilia or atypical lymphocytes) and internal organ involvement (liver is the most common). These manifestations are thought to be a type IV hypersensitivity with a delayed onset of usually 2–6 weeks after the initiation of drug therapy.1 2 While the pathogenesis of this condition is not well understood, mechanisms such as detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation and reactivation of Epstein-Barr virus and human herpesvirus 6 and 7 have been proposed.2 The most common drugs associated with DRESS syndrome are the aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine) and sulfonamides.3

A 62-year-old man with poorly controlled diabetes and subacute osteomyelitis presented to the hospital with fatigue, fever and anorexia. Prior...

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Flexion deformity of the finger caused by tophaceous gout of the flexor tendon

Description

A 53-year-old, right-handed man was referred to orthopaedic clinic with a 1-year history of progressive 'trigger-like' symptoms and eventual locking of the right ring and middle fingers. There was no history of trauma or joint problems. Medical history included stable chronic kidney disease and well-controlled hypertension. On examination of the right hand, there was limited passive mobility with complete flexion of the ring and middle fingers by 100° at the proximal interphalangeal joint, and additionally the ring finger by 45° at the distal interphalangeal joint. The left hand was unaffected. Furthermore, in the context of a raised serum uric acid concentration of 767 μmol/L 3 years previously, two palpable, non-tender nodules were found on the left olecranon.

Surgical exploration of the right ring finger found multiple small, white speckled deposits infiltrating the flexor tendon from the first annular pulley (A1) to just beyond the A3 pulley (

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Atypical presentation of false asystole detection in implantable loop recorder

Description

A 57-year-old male patient was admitted for evaluation of pacemaker explantation 7 years after implantation because of paroxysmal complete atrioventricular (AV) block due to presumed lyme carditis. In view of a stable ventricular pacing rate of <1%, complete removal of the system without reimplantation was considered. An electrophysiological study revealed normal AV conduction and normal AVBCL (atrioventricular block cycle length). Therefore, pacemaker removal and lead extraction were scheduled, the pacemaker was set to a VVI 30/min mode and a newer generation implantable loop recorder (ILR, Medtronic Reveal LINQ, Medtronic, Dublin, Ireland) was implanted for remote monitoring of the patient's heart rhythm. At a regular outpatient visit 2 weeks later, the ILR indicated an episode of asystole over 7.8 s (figure 1) during the daytime 1 day after ILR implantation. The patient did not report any symptoms at that time. Pacemaker interrogation showed appropriate function. The episode was hence considered erroneous asystole...

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A garden of parathyroid adenomas

Despite improvements in parathyroidectomy success rates, patients with persistent primary hyperparathyroidism (PHPT) after initial surgery continue to challenge clinicians. Some of the challenges are due to ectopic parathyroid adenomas, including thymic, intrathyroidal, carotid sheath and mediastinal glands, and others are because of supernumerary glands. While uncommon in PHPT, multigland disease is also an important consideration in patients requiring reoperative surgery for persistent disease. For this reason, localisation studies including sestamibi, ultrasound, CT scan and venous sampling for abnormal glands may be an essential component of the preoperative workup. In this report, we describe an unusual case of a patient who required a total of four operations to cure PHPT arising from seven parathyroid adenomas.

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Descended right superior parathyroid adenoma mimicking as inferior adenoma in primary hyperparathyroidism

Description

A 22-year-old woman presented with generalised bony pains over past 2 years. Clinical examination was unremarkable, and blood biochemistry revealed parathyroid hormone (PTH)-dependent hypercalcaemia, suggestive of primary hyperparathyroidism (albumin-corrected calcium –11 mg/dL (normal range 8.3–10.4); PTH –256 pg/mL (normal range 8–50)). Her creatinine was 0.8 mg/dL (normal range 0.6–1.2) and 25-OH vitamin D level was 31 ng/mL (30–75). She had low bone mass at distal end of radius (Z score of –2.8) and there was no evidence of renal stones. On localisation, both parathyroid scinitigraphy and ultrasound of neck localised the lesion to right inferior gland (figure 1A,B). There were no features of multiple endocrine neoplasia type 1.

Figure 1

(A)Parathyroid scintigraphy displaying an adenoma at right side. (B) Ultrasound neck showing right-sided adenoma.

She underwent focused right inferior parathyroidectomy, without intraoperative PTH (IOPTH) assay. Postoperatively,however, she had persistent hyperparathyroidism, and biopsy from the excised lesion revealed...

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Opaque intraocular lens for correction of intractable diplopia and torticollis

Description

A 72-year-old woman was referred to our hospital for treatment of persistent diplopia and bilateral large angle of esotropia (>50 prismatic dioptres): She had a 12-year previous history of double vision attributed to double paralysis of the VI nerve after a traffic accident. In order to avoid double vision, she permanently misplaced her head in torticollis by turning it all the way to the left. The left eye was the fixator and the view of the right eye was occluded by the nose (figure 1). Due to this, the patient suffered cervical contractures and experienced poor quality of life.

Figure 1

Torticollis and large bilateral esotropia.

On examination, best-corrected visual acuities were 20/70 in the right eye and 20/30 in the left eye. Orthoptic assessment revealed a complete paralysis of both VI cranial nerves with total absence of abduction. The...

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Dialysis-associated steal syndrome with limb ischaemia

Description

A 62-year-old man with end-stage renal failure on dialysis was referred to our hospital with worsening pain and ulceration in his right arm. He was started on haemodialysis 6 months ago, once his newly created brachiocephalic fistula was matured. Previously, he had been on peritoneal dialysis for over 2 years and was transitioned to haemodialysis after multiple catheter-site infections and peritonitis. His medical history was significant for poorly controlled hypertension and hypercholesterolaemia. On physical examination, necrosis of the skin and subcutaneous tissue localised to the right forearm and hand was evident (figure 1), along with dry gangrene of the fourth digit (figure 2). Right radial and ulnar artery pulses were absent. The arm distal to the fistula was cool, with decreased capillary refill and decreased sensation. Continuous handheld Doppler revealed exceptionally low radial and ulnar artery pulse signals and absence of flow at the digital...

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Challenging airway in a paediatric patient impaled by a freezer pop stick

Description

As experts of the human airway, it is our job as anaesthesiologists to control and secure the airway in the safest way possible for the patient. The perioperative anaesthetic plan always includes an airway component, ranging from bag-mask ventilation to endotracheal intubation. Routine surgical procedures may warrant a certain standardised airway strategy that may vary among institutions. However, there exist situations that are less common, in which standard airway practice is unclear. If the injury is suspected to be in a highly sensitive area and securing an airway may compromise or cause further injury, radiographic imaging may be warranted.1

Figure 1 depicts a paediatric patient impaled in the soft palate of the left oropharynx by a freezer pop stick that the patient had been previously enjoying and accidentally fell onto. (left of image). The CT scan portion of the figure is a contrast CT...

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Phase I/II Study of Pralatrexate in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Summary

Pralatrexate is a novel antifolate approved in the United States for the treatment of relapsed or refractory peripheral T-cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we conducted a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7-week cycle. All patients received concurrent vitamin B₁₂ and folic acid. In phase I, three patients received pralatrexate 30 mg/m² and none experienced a dose-limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1-9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut-off, median progression-free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia and mucositis (20%, each). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results demonstrate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. This trial was registered with ClinicalTrials. gov (NCT02013362).

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ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells

Summary

Long-chain acyl-coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen-responsive gene involved in the generation of fatty acyl-CoA esters. ACSL3 is expressed in both androgen-sensitive and castration-resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen-dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo-keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen-inactivating enzyme UDP-glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3-overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone-sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3-overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e., promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).

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microRNA-219-5p inhibits epithelial-mesenchymal transition and metastasis of colorectal cancer by targeting LEF1

Abstract

Aberrant expression of microRNAs (miRs) has been shown to play a critical role in the pathogenesis and progression of tumors. miR-219-5p has been reported to be abnormally expressed in some types of human tumors. However, the mechanism between miR-219-5p and colorectal cancer (CRC) metastasis remains unclear. In this study, miR-219-5p was found to be downregulated in CRC tissue compared with matched normal tissue. Through luciferase reporter assay, we demonstrated lymphoid enhancer-binding factor 1 (LEF1) as a direct target of miR-219-5p. Over-expression of miR-219-5p could inhibit motility, migration and invasion of CRC cells, and inhibit epithelial-mesenchymal transition (EMT). Furthermore, silencing LEF1 phenocopied this metastasis-suppressive function. The recovery experiment showed that re-expression of LEF1 rescued this suppressive effect on tumor metastasis and reversed the expression of EMT markers caused by miR-219-5p. Additionally, we demonstrated that miR-219-5p exerted this tumor-suppressive function by blocking the activation of the AKT and ERK pathways. Finally, nude mice experiment showed that miR-219-5p reduced the lung metastasis ability of CRC cells. Taken together, our findings indicate that miR-219-5p inhibits metastasis and EMT of CRC by targeting LEF1 and suppressing the AKT and ERK pathways, which may provide a new antitumor strategy to delay CRC metastasis.

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Influence of early phase clinical trial enrollment on patterns of end-of-life care for children with advanced cancer

Abstract

We conducted a retrospective cohort study of 125 pediatric oncology patients who died in 2010–2014 to explore how healthcare utilization, pediatric palliative care (PPC) receipt, and end-of-life care (EOLC) differed between patients enrolled in early phase clinical trials (EP) and those not enrolled (NEP). Baseline characteristics and healthcare utilization did not significantly differ between groups. EP patients received PPC consultation closer to death than NEP patients (median days before death = 58 [interquartile range = 16–84] vs. 85 [32–173]; P = 0.04). Our findings suggest that early phase trial enrollment does not substantially alter EOLC for children with advanced cancer but may contribute to later PPC engagement. Future studies should definitively assess the relationship between trial enrollment and PPC timing.

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Monitoring of plexiform neurofibroma in children and adolescents with neurofibromatosis type 1 by [18F]FDG-PET imaging. Is it of value in asymptomatic patients?

Abstract

Purpose

About 10% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumours (MPNST) mostly arising in plexiform neurofibroma (PN); 15% of MPNST arise in children and adolescents. 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG)-PET (where PET is positron emission tomography) is a sensitive method in differentiating PN and MPNST in symptomatic patients with NF-1. This study assesses the value of [¹⁸F]FDG-PET imaging in detecting malignant transformation in symptomatic and asymptomatic children with PN.

Methods

Forty-one patients with NF-1 and extensive PN underwent prospective [¹⁸F]FDG imaging from 2003 to 2014. Thirty-two of the patients were asymptomatic. PET data, together with histological results and clinical course were re-evaluated retrospectively. Maximum standardised uptake values (SUVmax) and lesion-to-liver ratio were assessed.

Results

A total of 104 examinations were performed. Mean age at first PET was 13.5 years (2.6–22.6). Eight patients had at least one malignant lesion; four of these patients were asymptomatic. Two of four symptomatic patients died, while all patients with asymptomatic malignant lesions are alive. All malignant tumours could be identified by PET imaging in both symptomatic and asymptomatic patients. All lesions judged as benign by [¹⁸F]FDG imaging and clinical judgment were either histologically benign if removed or remained clinically silent during follow-up. SUVmax of malignant and benign lesions overlapped, but no malignant lesion showed FDG uptake ≤3.15. Asymptomatic malignant lesions were detected with a sensitivity of 100%, a negative predictive value of 100% and a specificity of 45.1%.

Conclusion

Malignant transformation of PN also occurs in asymptomatic children and adolescents. Detection of MPNST at early stages could increase the possibility of oncologically curative resections.

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